A well-known problem in treatment of neurological disorders is ineffective delivery of therapeutic agents to neurons and associated cells due to the blood-brain and blood-nerve barriers. Considerable development has gone into the development of drugs and delivery systems for the transport of pharmacologically active species to overcome this limitation. To date, while several approaches have shown promise, surprisingly little therapeutic progress has been made with respect to delivery of a therapeutic agent to treat neurological conditions or diseases where transport to a target cell is inhibited by the blood-brain and blood-nerve barriers.
In particular, there are inherent difficulties in the effective administration of peptide therapeutic agents and/or their derivative, or analogs. Peptides often do not easily cross the blood brain barrier and, accordingly, their activity in the central nervous system after oral or parenteral administration is generally inhibited. In addition, many peptide agents have activity at sites external to the central nervous system which may contribute to clinical side effects. Since higher doses are required to create a therapeutic effect because of poor penetration of the blood brain barrier, a frequent consequence is that the higher doses may increase systemic toxicity and/or undesired side effects.
Extra-CNS side effects noted with the systemic administration of peptide agents can be largely averted by utilizing intrathecal drug delivery since intrathecal delivery to the lumbar or mid-thoracic spinal intrathecal space concentrates the medication in the lower area of the spinal cord cerebrospinal fluid at much higher levels than those attainable via the oral route of administration (Meythaler, McCary, Hadley, J. Neurosurg. 1997; 87(3):415-9). Typically, the type of delivery system for intrathecal therapy consists of a subcutaneously placed pump having a reservoir which is attached to an intraspinal catheter. This drug delivery methodology concentrates the medication within the spinal subarachnoid space and the thoracolumbar and sacral spinal regions at a much higher level than that attainable via the oral route of administration. Meythaler et al., J. NeuroSurgery 1997; 87:415-9. From the subarachnoid space, the cerebrospinal fluid then flows to the arachnoid villi for reabsorption thereby avoiding a significant part of the cerebral hemispheres. Meythaler et al., Arch. Phys. Med. Rehabil. 1996; 77:461-466. Only low levels of the medication have the potential to reach the brainstem or cerebrum as studies have demonstrated the lumbar-to-cisternal drug cerebrospinal fluid (CSF) drug concentration gradient is 4.1:1. Kroin et al., Parenteral Drug Therapy in Spasticity and Parkinson's Disease 1991, pp. 73-83. By utilizing intrathecal drug delivery, the cognitive side effects of oral drug delivery, such as drowsiness and lethargy, can be avoided. Coffey et al., J. Neurosurg. 1993; 78:226-232; Penn et al., N. Engl. J. Med. 1989; 320:1517-1522; Knuttson et al., J. Neurol. Sci. 1974; 23:473-484. Furthermore, intraventricular delivery does the same for the periventricular area or region of the brain.
Despite certain advantages of the intrathecally delivered peptide agents, patients often prefer an oral or systemically administered therapeutic agent as less invasive, particularly where the condition is chronic. Further, many peptides have beneficial and desirable effects on cells external to the CNS, such that simultaneous treatment of disorders in both the CNS and external to the CNS is desirable and may be addressed by systemic administration of a composition.
Thus, there exists a need for improved compositions for systemic, intrathecal and/or intraventricular delivery of a peptide therapeutic agent.